RESEARCH ARTICLE

Dose-Dependent Effect of Granulocyte Transfusions in Hematological Patients with Febrile Neutropenia Luciana Teofili*☯, Caterina Giovanna Valentini☯, Roberta Di Blasi, Nicoletta Orlando, Luana Fianchi, Gina Zini, Simona Sica, Valerio De Stefano, Livio Pagano Institute of Hematology, Catholic University, Rome, Italy ☯ These authors contributed equally to this work. * [email protected]

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OPEN ACCESS Citation: Teofili L, Valentini CG, Di Blasi R, Orlando N, Fianchi L, Zini G, et al. (2016) Dose-Dependent Effect of Granulocyte Transfusions in Hematological Patients with Febrile Neutropenia. PLoS ONE 11(8): e0159569. doi:10.1371/journal.pone.0159569 Editor: Nades Palaniyar, The Hospital for Sick Children and The University of Toronto, CANADA Received: March 22, 2016 Accepted: July 4, 2016 Published: August 3, 2016 Copyright: © 2016 Teofili et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract It is still under debate whether granulocyte transfusions (GTs) substantially increase survival in patients with febrile neutropenia. We retrospectively examined data relative to 96 patients with hematological malignancies receiving 491 GTs during 114 infectious episodes (IE). Patients were grouped according to the median doses of granulocytes transfused during the infectious episode (low-dose group: 3.0x108 cells/Kg). The impact of clinical, microbiological and GT-related variables on the infection-related mortality (IRM) was investigated. The IRM was not influenced by the number of GTs or by the total amount of granulocytes received, whereas a dose-related effect of the median dose received for IE was detected at univariate analysis (IRM of 18.4% in the standard-dose group, 44.4% in the low-dose group and 48.4% in the high-dose group, p = 0.040) and confirmed at multivariate analysis (OR 3.7, IC 95% 1.5–8.9; 0.004 for patients not receiving standard doses of GTs). Moreover, patients receiving GTs at doses lower or greater than standard had increased risk for subsequent ICU admission and reduced overall survival. The dose-related effect of GTs was confirmed in bacterial but not in fungal infections. Preliminary findings obtained from a subgroup of patients candidate to GTs revealed that levels of inflammatory response mediators increase in a dose-related manner after GTs, providing a possible explanation for the detrimental effect exerted by high-dose transfusions. GTs can constitute a valuable tool to improve the outcome of infections in neutropenic patients, provided that adequate recipienttailored doses are supplied. Further investigations of the immunomodulatory effects of GTs are recommended.

Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: The study was funded by "Centro di ricerca sulle cellule staminali emopoietiche e terapie cellulari" of Università Cattolica del Sacro Cuore, and by Grant Linea D1 to Luciana Teofili and Livio Pagano. Competing Interests: The authors have declared that no competing interests exist.

Introduction Patients with cancer face prolonged periods of neutropenia. The risk of febrile neutropenia (FN) is particularly high in patients with hematological malignancies, especially in those older than 60 years [1]. In these cases fever is often the only manifestation of an underlying serious

PLOS ONE | DOI:10.1371/journal.pone.0159569 August 3, 2016

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Granulocyte Transfusions in Infections

infection; therefore, FN may be life-threatening, and these patients are candidates for inpatient management with IV broad-spectrum antibiotic therapy covering gram-negative pathogens [2–5]. All these precautions notwithstanding, the mortality for infections in hematological patients with neutropenia is still high [6]. Although the intuition to transfuse granulocytes from allogeneic donors in neutropenic patients dates back several decades [7], only the introduction of granulocyte-colony stimulating factor (G-CSF) as a mobilizing protocol has yielded adequate granulocyte apheresis products [8]. Nevertheless, despite the great number of studies conducted so far, it is still debated whether the transfusion of granulocyte products to treat or prevent life threatening infections results in a substantial survival increase [9–11]. Similarly, the recently concluded randomized controlled trial “Safety and Effectiveness of Granulocyte Transfusions in Resolving Infection in People with Neutropenia” (RING Study) failed to prove a true beneficial effect of granulocyte transfusions (GTs) [12]. Supportive care with GTs has been implemented in our center several years ago [13]. Over the years, however, PMN collection procedures have been standardized and clinical indications to GT therapy have been defined. In this study we revised the data relative to a large series of hematological patients consecutively treated with GTs in our department during FN episodes. It is generally acknowledged that at least 1-2x1010 granulocytes per transfusion should be given to elicit a therapeutic effect [14]. Therefore, provided that GTs significantly improve the infection outcome, patients receiving highest amounts of granulocytes should also maximally benefit from transfusions. Nevertheless, our initial results rapidly disproved our hypothesis, since patients surviving infections were receiving lesser amounts of polymorphonuclear cells (PMNs) than others. The European guidelines to the preparation, use and quality assurance of blood components recommend as standard dose of granulocyte apheresis products for adult patients 1.5–3.0x108 cells/Kg of the recipient’s body weight [15]. We therefore divided our patients in three groups according to the median dose received during the infectious episode (IE), i.e. lower, equivalent or greater than 1.5–3.0x108cells/Kg. Our results clearly show that different GT doses exert diverging effects on the infection outcome of hematological patients, suggesting that GTs can constitute a valuable tool to improve the outcome of infections in neutropenic patients, provided that adequate recipient-tailored doses are supplied.

Materials and Methods Study design We retrospectively analyzed the data of patients receiving at least one GT between January 2009 and December 2015 at our Hematology Department. Over the entire study period, the eligibility criteria for GTs were fever, an absolute neutrophil count (ANC) 60 years, sex, underlying disease, chemotherapy line, allogeneic hematopoietic stem cell transplantation (allo-HSCT), days with ANC

Dose-Dependent Effect of Granulocyte Transfusions in Hematological Patients with Febrile Neutropenia.

It is still under debate whether granulocyte transfusions (GTs) substantially increase survival in patients with febrile neutropenia. We retrospective...
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